Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood–brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability

Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury.

Looking Beyond ‘White Slavery’: Trafficking, the Jewish Association’s representation of ‘the potential victim’, and the dangerous politics of migration control in England, 1890-1910

This article seeks to revise Jo Doezema’s suggestion that ‘the white slave’ was the only dominant representation of ‘the trafficked woman’ used by early anti-trafficking advocates in Europe and the United States, and that discourses based on this figure of injured innocence are the only historical discourses that are able to shine light on contemporary anti-trafficking rhetoric. ‘The trafficked woman’ was a figure painted using many shades of grey in the past, with a number of injurious consequences, not only for trafficked persons but also for female labour migrants and migrant populations at large. In England, dominant organizational portrayals of ‘the trafficked woman’ had first acquired these shades by the 1890s, when trafficking started to proliferate amid mass migration from Continental Europe, and when controversy began to mount over the migration to the country of various groups of working-class foreigner. The article demonstrates these points by exploring the way in which the Jewish Association for the Protection of Girls and Women (JAPGW), one of the pillars of England’s early anti-trafficking movement, represented the female Jewish migrants it deemed at risk from being trafficked into sex work between 1890 and 1910. It argues that the JAPGW stigmatised these women, placing most of the onus for trafficking upon them and positioning them to a greater or a lesser extent as ‘undesirable and undeserving working-class foreigners’ who could never become respectable English women. It also contends that the JAPGW, in outlining what was wrong with certain female migrants, drew a line between ‘the migrant’ and respectable English society at large, and paradoxically endorsed the extension of the very ‘anti-alienist’ and Antisemitic prejudices that it strove to dispel.